This Small Grant Award (R03) Application is a request for funding to support the research activities necessary for Tony Buchanan, Ph.D. to collect preliminary data on the neural control of the human stress response, with the goal of developing an ongoing research program on this topic. Psychosocial stress plays a role in the development of many disease states. Animal research has implicated the amygdala, hippocampus, and prefrontal cortex in the control of the stress response. The neural control of the human stress response is not well understood; these projects will examine this issue in humans with damage to the amygdala, hippocampus, and prefrontal cortex. We will measure cortisol and autonomic indices (blood pressure, heart rate, heart rate variability, and respiration) of stress in these subjects in response to the Trier Social Stress Test, a widely used and standardized laboratory stressor. We will control for potential baseline differences in hormonal function by assessing the diurnal cycle of cortisol on a separate, stress free day. Measurement of responses to an orthostatic challenge will control for potential baseline group differences in autonomic nervous system activity. We predict that subjects with damage to the amygdala, hippocampus, or prefrontal cortex will show a diminished response to psychosocial stress compared to subjects with brain damage outside these target areas. Measures of cognitive appraisal of the stressor and subjective stress ratings will be collected to examine potential group differences in the perception of the stressor. We predict that group differences in stress responses are not due to baseline physiological functioning, but to differential subjective and/or physiological responses to psychosocial stress. Psychiatric disorders such as depression and posttraumatic stress disorder are characterized by disturbance in the amygdala, hippocampus, and prefrontal cortex. These diseases are also associated with alterations in stress physiology. A better understanding of the role of these neural structures in the stress response could increase our understanding of the role of stress in the development of mental illness with the potential for developing treatments for these diseases. This work is a novel extension of research with brain damaged subjects, incorporating the strengths of the Department of Neurology's Patient Registry, which provides an unequalled registry of patients with focal brain damage and the expertise in stress research of the principal investigator. [unreadable] [unreadable] [unreadable]